Ditans: a new prospective for the therapy of migraine attack?

INTRODUCTION: Migraine attack is characterized by disabling pain and associated symptoms. Triptans represent the "gold standard" therapy, but cardiac subjects have significant limitations for this approach. New drug families are under consideration to expand therapeutic offerings, especially in the presence of contraindications or for non-responsive patients. This review aimed to analyze studies related to the category of "ditans," with a focus on lasmiditan, which is available for human use. MATERIALS AND METHODS: We consulted PubMed/MEDLINE, Web of Science, and www. CLINICALTRIALS: gov to find both original and review articles on the mechanism of action of 5-HT1F agonists in migraine, and for randomized, double-blind, placebo-controlled trials (RCTs) on the family of drugs called "ditans," with a focus on "lasmiditan," published in the time frame of 01-Jan-2010 to 31-Mar-2022. Only studies conducted in human subjects and published in English were included in this review. RESULTS: We retrieved four RCTs (named SAMURAI, SPARTAN, GLADIATOR, and CENTURION) and several studies that analyzed the efficacy and safety of lasmiditan. Lasmiditan at increasing doses showed significant improvement in pain and most other troublesome symptoms at 2 h. Adverse events were mild and mainly represented by dizziness, vertigo, drowsiness, and fatigue. No vasoconstrictive effects were described, suggesting the use of ditans as a safe option in chronic cardio- and cerebro-vascular disease. DISCUSSION: Lasmiditan could be a viable alternative to triptans, although further RCT studies and real-world evidence are needed to better understand its potential and possible adverse events in a larger population.

Efficacy and safety of reperfusion treatments in middle-old and oldest-old stroke patients.

INTRODUCTION: Intravenous thrombolysis (IT) and mechanical thrombectomy (MT) have significantly changed the clinical outcome of acute ischaemic stroke (AIS). Concerns about possible complications often reduce the use of these treatment options for older patients, preferentially managed with antiplatelet therapy (AT). Aim of this study was to evaluate, in a population of middle-old (75-84 years) and oldest-old (≥ 85 years) subjects, the efficacy and safety of different treatments for AIS (IT, IT + MT, MT or AT), mortality and incidence of serious complications. PATIENTS AND METHODS: All patients aged over 75 years admitted for AIS in two Stroke Units were enrolled. The physician in each case considered all treatment options and chose the best approach. NIHSS and modified Rankin Scale (mRS) were obtained and differences between admission and discharge scores, defined as delta(NIHSS) and delta(mRS), were calculated. The relationship between delta(NIHSS), delta(mRS) and type of procedure was analysed with a GLM/Multivariate model. Differences in mortality and incidence of serious complications were analysed with the chi-square test. RESULTS: A total of 273 patients, mean age 84.07 (± 5.47) years, were included. The Delta(NIHSS) was significantly lower in patients treated with AT than in those treated with IT and MT (p < 0.009 and p < 0.005, respectively). Haemorrhagic infarction occurrence was significantly lower (p < 0.0001) among patients treated with AT (10.6%) or IT (16.7%) compared to MT (34.9%) or MT + IT (37.0%). No significant difference was observed for in-hospital mortality. Age did not influence the outcome. CONCLUSIONS: Our results suggest that IT and AT are effective and relatively safe approaches in middle-aged and older patients.

Gender differences in obsessive-compulsive disorder traits among chronic migraine patients.

BACKGROUND: Psychiatric illnesses are often associated with severe forms of headache as chronic migraine (CM) with medication overuse headaches (MOH). Few data are available about obsessive-compulsive disorders (OCD) in migraineurs. This study aimed to investigate OCD traits in CM with MOH patients of both sexes and the impact on migraine treatment. METHODS: We enrolled all consecutive patients with CM and MOH treated with onabotulinumtoxin-A (OBT-A) in our Headache Center. Each subject was submitted to the Obsessive-Compulsive Inventory-Revised (OCI-R) test at the start (T0) and after four OBT-A sessions (T1). Statistical analysis compared OCI-R results at T0 and T1 according to sex with the chi-square test. RESULTS: We analyzed a sample of 60 subjects (40 females, 66.7%). At T0, 25% of males and 37.5% of females had a normal profile while 60% of males and 22.5% of females presented pathologic OCD traits. At T1, 30% of males and 60% of females were normal, while 40% of males and 15% of females resulted frankly pathologic. The difference in the OCI-R distribution was significant at T0 (p = 0.024) and at T1 (p = 0.047). Both males and females underwent a significant increase in normalization rates at T1 (p < 0.05). CONCLUSION: We observed a significant OCD traits rate at baseline, moreover among men. Females showed a more significant improvement in OCD traits at T1. OBT-A confirmed its high efficacy on CM, with a migraine severity improvement in both genders and all the OCI-R classes. Psychological attitude in the management of migraine should be better investigated in future studies.

Carotid occlusion: Impact of cerebral hemodynamic impairment on cognitive performances.

OBJECTIVES: The aim of this study was to investigate whether the presence of carotid artery occlusion (CO) may be associated with different cognitive performances in relation to the side of the occlusion and its hemodynamic consequences. METHODS: During a 12-month period, 61 asymptomatic patients, 32 with right and 29 with left CO, were enrolled. Each patient underwent an assessment of cerebrovascular reactivity (CVR) to hypercapnia with transcranial Doppler (TCD) ultrasonography using the breath-holding index (BHI). Neuropsychological assessment evaluating performances of the hemisphere ipsilateral to CO were administered at entry (T0 ) and then repeated after 2 years (T1 ). RESULTS: Scores obtained at colored progressive matrices (CPM) and Rey Complex Figure Copy Test were significantly lower at T0 in patients with reduced BHI values ipsilateral to CO. Multivariate models showed that reduced BHI values were also associated to a significant decrease from T0 to T1 in scores obtained for CPM and Categorical Verbal Fluency tests, respectively, in patients with right (P = 0.002) or left CO (P = 0.004). CONCLUSIONS: These findings suggest that hemodynamic alterations could be involved in the reduction in cognitive function regulated by the hemisphere ipsilateral to CO. The assessment of CVR with TCD ultrasonography may be a reliable approach for the individuation of asymptomatic patients with CO at increased risk of cognitive deterioration.

Influence of chronotype on migraine characteristics.

BACKGROUND: The aim of this study was to investigate chronotype in migraine patients and possible influences on the clinical expression of the disease. METHODS: During a one-year period, all consecutive patients admitted to two third-level headache centres with a new diagnosis of migraine were enrolled in a cross-sectional study. All subjects were submitted to the Morningness-Eveningness Questionnaire (MEQ-SA) and then classified in five different categories, from late to early-rising chronotype. Differences and trends among MEQ-SA categories and years from migraine onset, attacks' intensity and frequency were analysed first with analysis of variance, then with a multivariate/generalized linear model. RESULTS: One hundred seventy one migraine patients were included. Early-rising patients showed a lower migraine attacks frequency and longer disease duration with respect to late-rising patients. The categorical variable containing the five circadian types was able to identify a significantly different trend both for the monthly attacks frequency and for the disease duration (p < 0.0001 and p < 0.0001, respectively, analysis of variance). The results were also confirmed after correction for main influencing variables (multivariate/generalized linear model). The intensity of migraine attacks was not influenced by chronotype. CONCLUSIONS: According to the results of the present study, chronotype seems to influence number and duration of migraine attacks. Although sleep-wake cycle is a well-recognized factor able to influence thalamic-cortical synchronization, it usually does not receive appropriate consideration during migraine patients' assessment.

Acute penile trauma: imaging features in the emergency setting.

In an emergency department, penile traumas are uncommon and a prompt diagnosis is necessary. Penile injury may result from penetrating and non-penetrating trauma. Non-penetrating injuries can produce cavernosal hematomas or fractures: if not treated promptly, these lesions can result in fibrosis or erectile dysfunction. Penile traumatic lesions need a clinical approach first, but a radiological study is often required: ultrasonography with color and spectral Doppler study is usually the first approach. In some cases, magnetic resonance imaging may be performed to better recognize even small discontinuity of the tunica albuginea. Radiologists have to be aware of the various radiological patterns of penile traumatic lesions, in order to establish a prompt and correct diagnosis.

Transcriptional regulation of adhesive properties of Bacillus subtilis to extracellular matrix proteins through the fibronectin-binding protein YloA.

Bacterial adherence to extracellular matrix proteins (ECMp) plays important roles during host-pathogen interaction, however its genetic regulation remains poorly understood. yloA of the model bacterium Bacillus subtilis shows high homology to genes encoding fibronectin-binding proteins of Gram-positive pathogens. Here, we characterized the regulatory network of YloA-dependent adhesive properties of the probiotic B. subtilis natto (Bsn). YloA-proficient, but not YloA-deficient, Bsn specifically bound to ECMp in a concentration-dependent manner and were proficient in biofilm formation. yloA expression showed a continuous increase in activity during the growth phase and decreased during the stationary phase. The transcription factors AbrB and DegU downregulated yloA expression during the logarithmic and stationary growth phases respectively. Analysis of the yloA promoter region revealed the presence of AT-rich direct and inverted repeats previously reported to function as DegU-recognized binding sites. In spo0A cells, yloA expression was completely turned off because of upregulation of AbrB throughout growth. Accordingly, DNase I footprinting analysis confirmed that AbrB bound to the promoter region of yloA. Interestingly, Bsn bound fibronectin with higher affinity, lower Kd, than several bacterial pathogens and competitively excluded them from binding to immobilized-fibronectin, a finding that might be important for the anti-infective properties of B. subtilis and its relatives.

Validation of a self-reported instrument to assess work-related difficulties in patients with migraine: the HEADWORK questionnaire.

BACKGROUND: The degree to which work-related difficulties are recognized in headache research is poor and often carried out with inadequate information such as "reduced ability to work as usual", which do not capture at all the variety of difficulties and the factors that impact over them. The aim of this paper is to present the validation of the HEADWORK questionnaire, which addresses the amount and severity of difficulties in work-related tasks and the factors that impact over them. METHODS: We developed a set of items based on a previous literature review and patients' focus groups and tested it on a wide set of patients with episodic and chronic migraine attending eight different Italian headache centers. HEADWORK factor structure was assessed with exploratory and confirmatory factor analysis; internal consistency and construct validity were addressed as well. RESULTS: The validation sample (N = 373) was mostly composed of patients with episodic migraine without aura (64.3%) and of females (81%). Factor analysis retrieved two different scales: "Work-related difficulties", composed of eleven items which explain 67.1% of the total variance, and "Factors contributing to work difficulties", composed of six items which explain 52.1% of the total variance. Both HEADWORK subscales have good measurement properties, with higher scores being associated to higher disability, lower quality of life, lower productivity, higher headache frequency and pain intensity. CONCLUSIONS: HEADWORK is a 17-item, two-scale questionnaire addressing the impact of migraine on work-related difficulties in terms of difficulties in general or specific skills, and the factors contributing to these difficulties, defined as negative impact on work tasks. It can be used to address disability weights for the purpose of calculating the burden of migraine, and to assess the balance between therapeutic and side effects of medication on productivity.

Raven coloured progressive matrices in migraine without aura patients.

Conflicting results emerged from studies investigating cognitive performances in migraine patients. Based on clinical and neuroradiological aspects, the possible involvement of executive functions has been especially taken into consideration. The aim of this study was to evaluate, in a population of subjects affected by migraine without aura (MwoA), frontal lobe cognitive functions. We enrolled all the consecutive patients affected by MwoA referred to our headache centre for a first evaluation. Each patient underwent a neuropsychological evaluation including Raven coloured progressive matrices (CPM). We collected variables as age, education, years of migraine, frequency of attacks and CPM scores. Relationship between continuous variables was explored with multiple regression lines, selecting the best-fitting trendline for each relationship. We obtained a final sample of 36 subjects (females: 62.5%; mean age: 42.25 ± 10.21 years). Patients had mean length of migraine history of 12.25 ± 11.00 years and a mean frequency of attacks of 8.06 ± 7.15 per month. Linear regression underlines a progressive decrease of CPM score with the increase of the migraine history's length (R 2 = 0.8871; p < 0.001), and the frequency of migraine attacks (R 2 = 0.3122; p < 0.05). Our findings suggest that pathological CPM scores can be associated with the severity of migraine. These data seem to confirm the hypothesis of an impairment of executive functions in MwoA. Different hypotheses to explain cognitive impairment in migraine have been postulated including the impact of the typical white matter lesions and a long history of drug abuse. The possible relevant clinical consequence of a full comprehension of this particular aspect related to migraine deserves further attention and consideration.

Glycosylated Hemoglobin and Functional Outcome after Acute Ischemic Stroke.

BACKGROUND: Diabetes mellitus (DM) is associated to an increased incidence of cerebral and myocardial infarction which could be reduced by long-term maintenance of optimal glycemic values. The aim of the study was to evaluate in diabetic patients with ischemic stroke the chronic glycemic status and its relationship with functional outcome. METHODS: We retrospectively identified consecutive diabetic patients hospitalized for acute ischemic stroke. Clinical and biochemical characteristics at admission were assessed. The outcome measures were the attainment of the recommended glycosylated hemoglobin A1 (HbA1c) level and the 3-month functional status according to the modified Rankin Scale score. RESULTS: Among the 112 enrolled patients, 39 (34.8%) met the recommended goal of HbA1c less than 7%. Higher education level was predictive of good prestroke glycemic control (adjusted OR 1.32 per year [95% CI 1.15-1.51], P < .001). At the 3-month evaluation, 44 (39.3%) patients were classified as having a poor outcome. After categorization of HbA1c values into tertiles, a dose-response relationship with poor functional recovery was found (P = .001). The suboptimal prestroke glycemic status was an independent predictor of unfavorable outcome (adjusted OR 6.22 [95% CI 1.94-19.98] for HbA1c ≥7%, P = .002). CONCLUSIONS: The management of DM was suboptimal in nearly two thirds of diabetic subjects presenting with acute ischemic stroke. The glycemic control before stroke occurrence was an independent prognostic factor and HbA1c values above the recommended goals increased the risk of unfavorable 3-month outcome. The improvement of DM management may be an effective strategy to either decrease the burden of cerebrovascular disease or influence its clinical course.

Acute Occlusion of the Percheron Artery during Pregnancy: A Case Report and a Review of the Literature.

OBJECTIVES: The Percheron artery (PA) is a rare variant vessel. Its acute occlusion can cause a bilateral symmetrical thalamic stroke, clinically manifested as a sudden alteration of consciousness that could vary from sleepiness to coma. In this paper, we illustrate a case of acute PA occlusion in a young, pregnant woman and present a review of the literature, focusing on the possible causes of the acute occlusion. METHODS: A 35-year-old woman, at the fourth week of pregnancy, came to the emergency department of our hospital because of a sudden onset and persistent loss of consciousness. Brain magnetic resonance imaging (MRI) showed a symmetrical and bilateral thalamic infarction without evidence of other ischemic lesions, compatible with an acute PA occlusion. RESULTS: The patient, who showed full clinical recovery within a few hours of symptom onset, received a short-term anticoagulant treatment followed by aspirin for long-term prevention. CONCLUSIONS: We reviewed the literature about the possible causes of acute PA occlusion. This ischemic condition is usually associated with cardioembolic or small-vessel disease. However, in our patient, we did not find any element supportive for coagulative alteration or embolyzing conditions. PRACTICE: The presence of this type of thalamic stroke should be considered in the management of persistent loss of consciousness. PA occlusion is rare, but it needs a brain MRI examination for a correct diagnosis, a narrow evaluation of all the possible causes, and a long-term anticoagulant therapy. Pregnancy itself should constitute a rare but possible cause of a PA occlusion.

Metabolic syndrome and cerebrovascular impairment in Alzheimer's disease.

OBJECTIVE: Metabolic Syndrome (MeS) has inconstantly been associated with cognitive impairment. The aim of this study was to investigate the influence of MeS on cerebrovascular reactivity and the possible consequences on cognitive impairment in patients with Alzheimer's disease (AD). METHODS: A total of 162 AD patients were enrolled and grouped depending on the presence/absence of MeS. An ultrasound assessment of the neck vessels was performed to evaluate common carotid artery intima-media thickness (IMT). Cerebral hemodynamics was assessed by the transcranial Doppler-based breath-holding index (BHI) test. The relationship between BHI and MeS was explored first with a nested binary logistic model and then with a general linear model/adjusted model. Both models were corrected for sex, age, education, BMI, smoking attitude, and IMT treated as covariates. RESULTS: Pathologic BHI values were significantly more frequent among patients with MeS (risk ratio (RR):1.477; 95% CI: 1.177-1.848). MeS significantly improved the prediction of a pathologic BHI in the binary logistic model (odds ratio (OR):11.64; 95% CI: 1.001-135.304; p < 0.05). Moreover, AD patients affected by MeS had significantly lower mean Mini-Mental State Evaluation values than the unaffected ones (16.06; 95% CI: 14.96-17.15 vs 17.79; 95% CI: 17.05-18.53; p < 0.0001). CONCLUSIONS: Our data show an association between the presence of MeS and cerebral hemodynamics. The possibility that a cluster of potentially treatable vascular risk factors may influence AD patients' prognosis deserves consideration.

Flaccid penile acceleration as a marker of cardiovascular risk in men without classical risk factors.

INTRODUCTION: Conventional cardiovascular (CV) risk factors identify only half of subjects with incident major adverse CV events (MACE). Hence new markers are needed in high CV risk subjects, as those with erectile dysfunction (ED). A role for dynamic peak systolic velocity (D-PSV) at penile color Doppler ultrasound (PCDU) has been suggested, but it is operator dependent and time consuming. Flaccid penile acceleration (FPA) is a PCDU parameter that reflects PSV, the systolic rise time (SRT), and end diastolic velocity (EDV), arithmetically defined as (PSV-EDV)/SRT. AIM: The study aims to verify, in a large series of ED patients, whether FPA has a role in predicting MACE. METHODS: A selected series of 1,903 patients (aged 54.6 ± 11.7) with a suspected organic component for ED was retrospectively studied from January 2000 until July 2012. A subset of this sample (n = 622) was enrolled in a longitudinal study that ended in December 2007. MAIN OUTCOME MEASURES: Several clinical, biochemical, and instrumental (PCDU) parameters were studied. RESULTS: Decreased FPA levels were associated with worse metabolic profile and sexual symptoms. In addition, FPA was positively associated with both total and calculated free testosterone. In the longitudinal study, unadjusted incidence of MACE was significantly associated with lower baseline FPA. When FPA was introduced in a multivariate model, along with D-PSV, after adjusting for age and Chronic Disease Score, lower FPA, but not D-PSV, was associated with incident MACE in lower--risk-i.e., younger (HR = 0.48 [0.23-0.99]), nonhypertensive (HR = 0.59 [0.38-0.92]), nonobese (HR = 0.68 [0.49-0.96]), or nondiabetic (HR = 0.67 [0.49-0.96] subjects; all P < 0.05--but not in higher-risk ones. FPA demonstrated a threshold effect in predicting MACE at a value <1.17 m/s(2) which showed a threefold increase in incidence of MACE in apparently lower-risk individuals. CONCLUSIONS: FPA is an easily obtained PCDU parameter and capable of identifying adverse metabolic and CV profiles, particularly in apparently lower-risk individuals with ED.

Instrumental exams performance can be a contributing factor to the delay in diagnosis of migraine.

BACKGROUND: Diagnostic delay is a recognized drawback for a correct management of migraine patients. The aim of this study was to investigate the possible relationship among number and type of examinations performed and diagnostic delay in migraine diagnosis. METHODS: We enrolled 500 subjects referred to our Headache Center for a migraine without aura. We analyzed the relationship among diagnostic delay, number of examinations performed and performance of each single test by a Cox regression model and an ordinal logistic regression model. RESULTS: Each individual exam increased a diagnostic delay of at least 12 months (p < 0.05, Cox regression model). Brain CT as the first diagnostic approach had a reduced risk of delay of more than 5 years (OR 0.632, 95% CI 0.71-0.56, p < 0.05, ordinal regression model). CONCLUSIONS: The number of instrumental examinations seems to significantly influence the diagnostic delay. This aspect contributes to increase health care costs, the risk of pain chronicization and pharmacological treatment misuse.

Impact of carotid stenosis on the outcome of stroke patients submitted to reperfusion treatments: a narrative review.

Intravenous thrombolysis (IT) and mechanical thrombectomy (MD) are the two interventional approaches that have changed the outcome of patients with acute ischemic stroke (AIS). Ipsilateral and contralateral carotid stenosis (ICS, CCS) play an important role in regulating cerebral hemodynamics, both in chronic and acute situations such as AIS. Several studies have explored their role in the incidence and severity of stroke, but very few have investigated the possible impact of ICS and CCS on the efficacy of interventional procedures. The purpose of this review was to I) highlight the incidence and prevalence of carotid stenosis (CS); II) assess the impact of ICS and CCS on cerebral hemodynamics; III) evaluate the effect of carotid stenosis on the efficacy of interventional therapies (IT and MT) for AIS; and IV) report therapeutic complications related to CS. We searched PubMed/Medline for case reports, reviews, and original research articles on English-language review topics during the period from January 1, 2000 to October 1, 2023. CS is associated with 15-20 % of the total number of AIS. ICS and CCS had a negative influence on both cerebral hemodynamics before AIS and outcome after interventional procedures (IT, MT alone or in bridging). Available data on cerebral hemodynamics and efficacy of interventional therapies for AIS suggest a negative role of CS. Therefore, early diagnosis of CS may be considered relevant to preventive and post-stroke treatment strategies.

Impact of Inducible Nitric Oxide Synthase Activation on Endothelial Behavior under Magnesium Deficiency.

Endothelial dysfunction is a crucial event in the early pathogenesis of cardiovascular diseases and is linked to magnesium (Mg) deficiency. Indeed, in endothelial cells, low Mg levels promote the acquisition of a pro-inflammatory and pro-atherogenic phenotype. This paper investigates the mechanisms by which Mg deficiency promotes oxidative stress and affects endothelial behavior in human umbilical vascular endothelial cells (HUVECs). Our data show that low Mg levels trigger oxidative stress initially by increasing NAPDH oxidase activity and then by upregulating the pro-oxidant thioredoxin-interacting protein TXNIP. The overproduction of reactive oxygen species (ROS) activates NF-κB, leading to its increased binding to the inducible nitric oxide synthase (iNOS) promoter, with the consequent increase in iNOS expression. The increased levels of nitric oxide (NO) generated by upregulated iNOS contribute to disrupting endothelial cell function by inhibiting growth and increasing permeability. In conclusion, we provide evidence that multiple mechanisms contribute to generate a pro-oxidant state under low-Mg conditions, ultimately affecting endothelial physiology. These data add support to the notion that adequate Mg levels play a significant role in preserving cardiovascular health and may suggest new approaches to prevent or manage cardiovascular diseases.

Effects of prophylactic drug therapies and anti-calcitonin peptide-related monoclonal antibodies on subjective sleep quality: An Italian multicenter study.

OBJECTIVE/BACKGROUND: sleep alterations strongly influence migraine severity. Prophylactic therapies have a major impact on migraine frequency and associated symptoms. The study purpose was to compare the impact of oral drug therapies or gene-related anti-calcitonin monoclonal antibodies (anti-CGRP mAbs) on sleep alterations. We also evaluated which drug therapies are more effective on sleep quality and the different impact on migraine frequency and life quality. PATIENTS/METHODS: this is a multicenter, prospective study conducted in three specialized headache centers (Marche Polytechnic University, Ancona; University of Palermo, Palermo; Fondazione Policlinico Campus Bio-Medico, Rome). At baseline, we assigned migraine patients to preventive therapy with first-line drugs or anti-CGRP mAbs. The Pittsburgh Sleep Quality Index (PSQI) and Migraine Disability Assessment (MIDAS) scales were administered. After three months, we re-evaluated the patients with the same scales. RESULTS: 214 patients were enrolled. Any prophylaxis was significantly associated with a reduction in PSQI score (mean difference 1.841; 95%CI:1.413-2.269; p < 0.0001), most significantly in the anti-CGRP mAb group (mean difference 1.49; 95%CI:2.617-0.366; p = 0.010). Anti-CGRP mAbs resulted in significant improvement in migraine severity and MIDAS scores. Among oral therapies, calcium antagonists and antidepressants were the most effective in reducing PSQI score between T0 and T1 (p = 0.042; p = 0.049; p < 0.0001, respectively). CONCLUSIONS: anti-CGRP mAbs revitalized the management of migraine with stable and well-documented efficacy. Our data also suggest that anti-CGRP mAbs result in a positive effect on sleep quality, with a significant improvement in PSQI scores. Knowing the relevant impact of sleep disruption on migraine severity, these data could help for the management of migraine patients.

Prognostic value of plasma lactate levels among patients with acute pulmonary embolism: the thrombo-embolism lactate outcome study.

STUDY OBJECTIVE: We investigate the prognostic value of plasma lactate levels in patients with acute pulmonary embolism. METHODS: We studied adult patients with symptomatic, objectively confirmed pulmonary embolism presenting to a single emergency department. Plasma lactate and troponin I levels were tested at presentation. We considered lactate values greater than or equal to 2 mmol/L and troponin I values greater than or equal to 0.10 ng/mL to be abnormal. Right-sided ventricular dysfunction was assessed by echocardiography. Primary endpoint was all-cause death occurring on or before 30 days after presentation. Secondary endpoints were the composite of all-cause death and clinical deterioration (defined as progression to shock, mechanical ventilation, or cardiopulmonary resuscitation) and death caused by pulmonary embolism. We tested the association between lactate level greater than or equal to 2 mmol/L and the endpoints using Cox proportional hazards regression analysis. RESULTS: Of the 270 patients included in the study, the mean age was 73 years (SD 12.7 years) and 151 (55.9%) were women. Twelve patients (4.4%) showed shock or hypotension (shock or systolic arterial pressure <100 mm Hg) at presentation, 109 (40.4%) had right-sided ventricular dysfunction, 93 (34.4%) showed troponin I level greater than or equal to 0.10 ng/mL, and 81 (30%) showed lactate level greater than or equal to 2 mmol/L. Seventeen patients (6.3%) died, 12 (4.4%) because of pulmonary embolism, and 37 (13.7%) reached the composite endpoint. Patients with lactate level greater than or equal to 2 mmol/L showed higher mortality (17.3%; 95% confidence interval [CI] 11.9% to 20%) than patients with a lower level (1.6%; 95% CI 0.8% to 1.9%). Plasma lactate level was associated with all-cause death (hazard ratio 11.67; 95% CI 3.32 to 41.03) and the composite endpoint (hazard ratio 8.14; 95% CI 3.83 to 17.34) independent of shock or hypotension, right-sided ventricular dysfunction, or elevation of troponin I values. CONCLUSION: Patients with pulmonary embolism and elevated plasma lactate level are at high risk of death and adverse outcome, independent of shock or hypotension, or right-sided ventricular dysfunction or injury markers.